DESCRIPTION: Antiviral therapy is effective in preventing AIDS in HIV-infected people. However, an increasing number of HIV infected individuals suffer or even die of diseases other than AIDS including cardiovascular diseases. The biology behind these clinical observations is not well understood, although both anti-retroviral therapy (ART) dependent and independent mechanisms appear to be involved. Here we plan to study a key mechanism by which HIV can cause endothelial activation and dysfunction, which are believed to precede atherosclerotic processes and also lymphatic vessel biology. Nef is known to play a pivotal role in HIV pathogenesis and to mediate its own transfer from T cells to bystander cells. In this proposal, we postulate that HIV-Nef can efficiently be transferred from T cells to other blood cells including vascular endothelial cells, which are in steady contact with flowing blood and lymph fluid. Indeed, we can show that transfer of Nef leads to endothelial cell activation and cell death which can be effectively inhibited by antioxidants, suggesting that antioxidants could be added to the treatment regimen of HIV-infected people on ART. Based on our preliminary data that HIV dependent endothelial activation is explained by transfer of Nef from blood cells to coronary arterial endothelial cells, we further hypothesize that transfer of Nef to vascular cells may lead o cardiovascular dysfunction and pathology of the cardiovascular system. Understanding the cellular trafficking and the signal transduction of Nef in the vascular wall is important because these processes involve all vascular cells, with the endothelium playing an important regulatory role. Thus, determining the cellular mechanism of Nef-induced vascular pathology in vascular bystander cells can help to identify HIV-Nef as a novel target for preventing and treating HIV-associated diseases.